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Review of Neurochemistry

What are neurotransmitters? _________________________________

In molecular terms, neurotransmitters are molecules that _______________ (______________) and _________________________ ofneurons by, for example, increasing or decreasing enzymatic activityor altering membrane properties.

Classes of molecules that serve as neurotransmitters:I. Small molecules:

A. Acetylcholine (very important at ______________________ inperipheral nervous system and other synapses in the brain - CNS).

B. Monoamines:a) Catecholamines1. Dopamine (Substantia Nigra in midbrain);2. Norepinephrine (noradrenaline) and Epinephrine (adrenaline)

- _____________________________________, respectively;b) Indoleamines1. Serotonin2. Histamine (found mostly in mammillary nuclei of hypothalamus)

C. Amino acids:a) Excitatory amino acids (ex., glutamate, aspartate, taurine)- glutamate most utilized excitatory NT; ex. cortical pyramidal cells.

b) Gamma-aminobutyric acid (GABA)- most widespread inhibitory neurotransmitter throughout the brain.

c) Glycine- inhibitory neurotransmitter, especially in _____________.- normally inhibits motor neuron activity.

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C. Purines1. ATP

II. Large NeurotransmittersNeuropeptides- there are at least 50 neuropeptides that act as neurotransmittersor neuromodulators (little direct activity by themselves, butmodulate action of other neurotransmitters).

- neuropeptides are normally short amino acid chains.- some examples of neuropeptides:

- Endorphins (endogenous opioid analgesics of the body).- Substance P (involved in pain neurotransmission).- Corticotropin-releasing hormone (CRH - stress & anxiety).- Neuropeptide Y (NPY - control of feeding).- Vasopressin (diuretic hormone - control of drinking).

III. Soluble Gases1. Nitric oxide2. Carbon monoxide

What’s Dale’s Principle? ______________________________________________________________________________________

Is this true? _____

What’s Dale’s Modified Principle? _____________________________________________________________________________________________________________________________________

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SYNTHESIS, PACKAGING, AND TRANSPORTOF NEUROTRANSMITTERS

1. Production controlled by _______ (cell types)2. Small neurotransmitter molecules; synthesized in ______________

(ex., acetylcholine, glutamate, GABA)3. Large neurotransmitter molecules (peptides); synthesized in _____

______ (ex., endorphins, Substance P)

Microtubules

Synapticvesicles(peptides)

Button

Synapticcleft

Golgicomplex

Mitochondrion

Dendriticspine

Presynpaticmembrane

Postsynpaticmembrane

Precursor

Synthesizingenzymes

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7 CRITERIA FOR SMALL NEUROTRANSMITTER STATUS

1. ______________________________2. ______________________________________3. ______________________________________________________4. ______________________________________5. ________________________6. ____________________________________7. _________________________________________________

NB. Most neurotransmitters are most accurately called “putative”(supposedly) neurotransmitters because all the above criteria aredifficult to obtain.

Neuropeptide status requires a different set of criteria:

1. Includes the development of ____________________ to detect theputative neuropeptide (includes extraction and separation ofendogenous peptide).

2. Determination of ______________________.3. __________________ of peptide to test for bioactivity.4. Production of ___________ to endogenous peptide to visualize and

localize neuropeptide in the central nervous system.

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RELEASE OF NEUROTRANSMITTERS

1. Arrival of _________________2. Opening of _________________________ channels3. Ca++ enters into presynaptic button (enters close to vesicles)4. Ca++ ________________________________5. Induces the ____________________ of synaptic vesicles to the

presynaptic membrane6. Exocytosis: neurotransmitter released into the ______________

What is quantal release? ______________________________________________________________________

Actionpotentialarrivessynaptic

vesicle

Ca++ enters cell

Vesicledocks tomembrane

Vesicle fuses NT released

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Neurotransmittervesicle exocytosis

Demonstration of neurotransmitterquantal release

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DEACTIVATION OF NEUROTRANSMITTERS

1. _____________________________________________(ex., amino acids and monoamines)

2. __________________________(ex., acetylcholinesterase for ACh, several specific and non-specific proteinases for breakdown of neuropeptides - endopeptidases)

3. Recycling (once back inside the presynaptic membrane)

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There exist 2 general types of neuronal transmission in the brain:

1. “Wiring transmission”: glutamate and GABA mediate ___________________ precise excitatory and inhibitory effects of one neuronon relatively few follower (other) neurons.

- spatially precise: ________________________________________

- temporally precise: ____________________________________________________________________________________________

Wiring transmission is very important for? ____________________________________________________________________________

Thus, wire transmission is nearly entirely mediated by ion channelreceptors, which can quickly depolarize or hyperpolarize neurons.

2. “Volume transmission”: monoamines (DA, NE, EPI, 5-HT) andneuropeptides mediate _____________________________ excitatoryand inhibitory effects of one neuron on a large number of followerneurons (ex. human substantia nigra of humans contains roughly10,000 neurons per side, but 1 DA neuron contacts 1000s of neurons)

- spatially imprecise: _______________________________________

- temporally imprecise: _____________________________________

Thus, monoamines are believed to play a role more in regulating thegeneral excitatory and inhibitory “tone” of their targets rather thanmediating specific transfer of sensory information or motor commands.

Volume transmission important for: __________________________________________________________________________________

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RECEPTORS AND RECEPTOR SUBTYPES

1. Receptors are proteins that contain binding sites for _______________________

2. “Lock and Key” arrangement

3. Receptor subtypes: Several receptor proteins can bind ________________ (ex., acetylcholine binds both “nicotinic” and “muscarinic”receptors).

4. Effect of a neurotransmitter is determined by the ________________________

X X

ligand

different brain regionsReceptor 1 Receptor 2

The only way that a neurotransmitter can produce an effect on atarget neuron is by _____________________.- every receptor protein has at least 2 important functional domains:A. _________________B. _________________

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TYPES OF RECEPTORS

1. ___________________

2. ____________________

- produces second-messenger moleculeswhich: - _____________________

- _________________________- ________________________________

outside

inside

outside

inside

There are two general types of receptors based on their type of effector domain:

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PSYCHOPHARMACOLOGY

The study of the effects of drugs on the nervous system and behavior

Drug (pharmacology):______________________________________________________________________________________________________________________________________________________

Exogenous : “produced from ________” (ex., aspirin)Endogenous : “produced from _______” (ex., acetylcholine)

What are Drug effects? _______________________________________________________________.

Drug = _______

In neuropharmacology, ligands can have two general effects on synaptic transmission; they can _______ or _____ neurotransmission.

- Drugs that facilitate the effects of a particular neurotransmitter are called __________.

- Drugs that inhibit the effects of a particular neurotransmitter are called _______________.

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General principles of drug action

Pharmacodynamics: _______________________________________________________________________.- for example, a drug may block or stimulate receptors, or enzymes

Pharmacokinetics: ____________________________________________________________________________________.- for example, drug solubility, rate of absorption, rate of metabolism.

Although pharmacodynamic factors determine the specific biologicaleffects of a drug, pharmacokinetic factors can be very important indetermining how effective a drug is (ex. why not use dopamine totreat Parkinson’s disease?).

I. Important pharmacokinetic considerations

A. How do drugs reach their site of action?- crossing a variety of biological barriers, for example:

1) The epithelial cell lining of the digestive tract -a. epithelial surface area is _______________________________than in the stomach, making it an area of choice for absorption.

b. Food ______ gastric emptying (stays in stomach longer), so it isoften recommended that drugs be taken on _______ stomachs toallow drug to reach the small intestines more quickly.

c. A similar principle works for alcohol. It is absorbed much moreefficiently in the small intestines than in the stomach so alcohol’seffects are ________________ when ingested on empty stomachs.

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2). The endothelial cell lining of blood vessels -a. outside the brain, _________________________ allow most small molecules to pass through (fat soluble or not). Only large proteins, or protein-bound molecules are excluded.

b. in the brain, ____________ of the endothelial cells, and astrocytesdo not allow even small particles to ______________ into the brain(________________). Only fat soluble molecules diffuse into brain.

3). Neuronal membranes -a. steroids are examples of drugs that act inside cells and must be able to cross the cell membrane. They are able to do so becausethey are ____________.

B. How do drugs cross biological barriers (issue of permeability)?1) _________________ – many small and fat-soluble molecules can

directly cross (diffuse) all cell membranes without assistance.-ex. water, some gases {O, CO, CO2, NO} and some small "uncharged"

molecules {such as alcohol and steroids}).- the net direction of movement = concentration gradient (high to low)

2) ____________________ – many molecules cross membranes via channels or transporters. These are proteins embedded in cell membranes that selectively allow molecules through

- ex. ion channels, neurotransmitter transporters.- net direction of movement from high to low concentration.

3) __________________ – molecules pumped against concentration gradient (from low to high concentration). These special proteins require energy (usually ATP) to carry out their task.

- ex.: the Na+-K+pump (ATPase)

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C. How are drugs inactivated and removed from the body (clearance)?Biotransformation/metabolism – many substances are changed chemically (___________) while in the body and in most cases these changes _______ the substance's biological activity and increases its ease of _________ in the urine.- liver enzymes play a large role in drug metabolism- blood circulation from digestive tract goes directly to ______- in order for drugs taken orally to be effective, they need to ______

_______________________________.

So, route of administration of a drug is a very important variable.

Some additional routes:- ____________ (im);- ____________ (sc);- __________;- _______

Different routes of administration

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There exist significant individual differences in pharmacokinetics that lead to substantial differences in sensitivity to pharmacological agents.

Examples of important individual factors:

- Body weight and size – smaller and lighter people tend to be more ________ to a particular dose of a drug (simply a ________ effect).

- Age – children and old people are usually more sensitive to a particular dose of a drug beyond body size

- infants may have ______ levels of certain enzymes involved in the metabolism of drugs.

- older individuals may also have ____________________ and their biological barriers may not be as efficient in _________ drugs from absorption and entry into tissues.

- Gender – besides the size component, women have a greater proportion of adipose tissues and a lower proportion of water than men.

- some fat-soluble drugs are taken up _________________________ ________ in women than men.

- Genetic – there are genetic differences in the __________________ __________.

- ex. individuals (especially of Asian descent) have a deficient form of the enzyme acetaldehyde dehydrogenase. This enzyme is important in the metabolism of alcohol, thus, people with a deficiency in this enzyme are much more sensitive to the "toxic" effects of alcohol, such as "flushing" of the face, sweating and nausea.

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II. Important pharmacodynamic considerations:

Mechanism of action – invariably, drug actions are produced by interactions with a __________________________________ present in cells.- for CNS drugs, the functional molecule that the drug interacts with is in many cases a protein (ex. receptor, ion channel, or enzyme).- drugs often produce more than one physiological effect. However, not all effects will display the same sensitivity (in other words the drug will be more potent at producing one vs. another effect).

Drug Potency vs. Efficacy

Potency: _______________________________________- related to “affinity” of drug for site of action

Efficacy: ______________________________

Drug A morepotent than B

Drug B moreefficacious than A

A

B

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A useful drug will be very potent for producing a desired effect and not very potent for producing an unwanted ____________.

Side-effects: ____________________________________________ _______________ (can be beneficial, but often detrimental)- ex., barbiturates are effective in reducing anxiety, but they alsoreduce respiratory rate, which can lead to death (very small therapeutic index).

- death is obviously the ultimate unwanted side-effect. Many drugs when given in a high enough concentration are _______.

- the lethality of a drug is often described as the ______ – the lethal dose in 50% of individuals. This can only be determined empirically (by experiment/observation). A "good" drug produces its desired effect at much lower concentrations than the LD50.

- the effective dose of a drug is often described as the ______ – the effective dose in 50% of individuals.

- the therapeutic ratio for a drug is = ______________.

- a very high therapeutic ratio is desired!!!

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Dose-response properties

ED50: Dose of drug at which 50% of maximal effect is achieved

LD50: Dose of drug at which 50% lethality is observed

Therapeutic Index: Ratio of LD50/ED50 (larger is better)

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ED50 LD50